tbuckley/cabot-search huggingface dataset:
ACT-Discover: identifying karyotype heterogeneity in pancreatic cancer evolution using ctDNA
Authors: Ariana Huebner, James R. M. Black, Francesca Sarno, Roberto Pazo, Ignacio Juez, Laura Medina, Rocio Garcia-Carbonero, Carmen Guillén, Jaime Feliú, Carolina Alonso, Carlota Arenillas, Ana Belén Moreno-Cárdenas, Helena Verdaguer, Teresa Macarulla, Manuel Hidalgo, Nicholas McGranahan, Rodrigo A. Toledo
Journal: Genome Medicine (2023)

Abstract Background Liquid biopsies and the dynamic tracking of somatic mutations within circulating tumour DNA (ctDNA) can provide insight into the dynamics of cancer evolution and the intra-tumour heterogeneity that fuels treatment resistance. However, identifying and tracking dynamic changes in somatic copy number alterations (SCNAs), which have been associated with poor outcome and metastasis, using ctDNA is challenging. Pancreatic adenocarcinoma is a disease which has been considered to harbour early punctuated events in its evolution, leading to an early fitness peak, with minimal further subclonal evolution. Methods To interrogate the role of SCNAs in pancreatic adenocarcinoma cancer evolution, we applied whole-exome sequencing of 55 longitudinal cell-free DNA (cfDNA) samples taken from 24 patients (including 8 from whom a patient-derived xenograft (PDX) was derived) with metastatic disease prospectively recruited into a clinical trial. We developed a method, Aneuploidy in Circulating Tumour DNA (ACT-Discover), that leverages haplotype phasing of paired tumour biopsies or PDXs to identify SCNAs in cfDNA with greater sensitivity. Results SCNAs were observed within 28 of 47 evaluable cfDNA samples. Of these events, 30% could only be identified by harnessing the haplotype-aware approach leveraged in ACT-Discover. The exceptional purity of PDX tumours enabled near-complete phasing of genomic regions in allelic imbalance, highlighting an important auxiliary function of PDXs. Finally, although the classical model of pancreatic cancer evolution emphasises the importance of early, homogenous somatic events as a key requirement for cancer development, ACT-Discover identified substantial heterogeneity of SCNAs, including parallel focal and arm-level events, affecting different parental alleles within individual tumours. Indeed, ongoing acquisition of SCNAs was identified within tumours throughout the disease course, including within an untreated metastatic tumour. Conclusions This work demonstrates the power of haplotype phasing to study genomic variation in cfDNA samples and reveals undiscovered intra-tumour heterogeneity with important scientific and clinical implications. Implementation of ACT-Discover could lead to important insights from existing cohorts or underpin future prospective studies seeking to characterise the landscape of tumour evolution through liquid biopsy.
Orthogonal cytokine engineering enables novel synthetic effector states escaping canonical exhaustion in tumor-rejecting CD8+ T cells
Authors: Jesus Corria-Osorio, Santiago J. Carmona, Evangelos Stefanidis, Massimo Andreatta, Yaquelin Ortiz-Miranda, Tania Muller, Ioanna A. Rota, Isaac Crespo, Bili Seijo, Wilson Castro, Cristina Jimenez-Luna, Leonardo Scarpellino, Catherine Ronet, Aodrenn Spill, Evripidis Lanitis, Pedro Romero, Sanjiv A. Luther, Melita Irving, George Coukos
Journal: Nature Immunology (2023)

To date, no immunotherapy approaches have managed to fully overcome T-cell exhaustion, which remains a mandatory fate for chronically activated effector cells and a major therapeutic challenge. Understanding how to reprogram CD8+ tumor-infiltrating lymphocytes away from exhausted effector states remains an elusive goal. Our work provides evidence that orthogonal gene engineering of T cells to secrete an interleukin (IL)-2 variant binding the IL-2Rβγ receptor and the alarmin IL-33 reprogrammed adoptively transferred T cells to acquire a novel, synthetic effector state, which deviated from canonical exhaustion and displayed superior effector functions. These cells successfully overcame homeostatic barriers in the host and led-in the absence of lymphodepletion or exogenous cytokine support-to high levels of engraftment and tumor regression. Our work unlocks a new opportunity of rationally engineering synthetic CD8+ T-cell states endowed with the ability to avoid exhaustion and control advanced solid tumors.
A simulation-based comparative effectiveness analysis of policies to improve global maternal health outcomes
Authors: Zachary J. Ward, Rifat Atun, Gary King, Brenda Sequeira Dmello, Sue J. Goldie
Journal: Nature Medicine (2023)

Abstract The Sustainable Development Goals include a target to reduce the global maternal mortality ratio (MMR) to less than 70 maternal deaths per 100,000 live births by 2030, with no individual country exceeding 140. However, on current trends the goals are unlikely to be met. We used the empirically calibrated Global Maternal Health microsimulation model, which simulates individual women in 200 countries and territories to evaluate the impact of different interventions and strategies from 2022 to 2030. Although individual interventions yielded fairly small reductions in maternal mortality, integrated strategies were more effective. A strategy to simultaneously increase facility births, improve the availability of clinical services and quality of care at facilities, and improve linkages to care would yield a projected global MMR of 72 (95% uncertainty interval (UI) = 58–87) in 2030. A comprehensive strategy adding family planning and community-based interventions would have an even larger impact, with a projected MMR of 58 (95% UI = 46–70). Although integrated strategies consisting of multiple interventions will probably be needed to achieve substantial reductions in maternal mortality, the relative priority of different interventions varies by setting. Our regional and country-level estimates can help guide priority setting in specific contexts to accelerate improvements in maternal health.
Arterial wall inflammation assessed by 18F-FDG-PET/CT is higher in individuals with Type 1 diabetes and associated with circulating inflammatory proteins
Authors: Anna W M Janssen, Julia I P van Heck, Rinke Stienstra, Erik H J G Aarntzen, Janna A van Diepen, Niels P Riksen, Cees J Tack
Journal: Cardiovascular Research (2023)

The article investigates whether chronic hyperglycaemia in Type 1 diabetes (T1D) is associated with a proinflammatory immune signature and with arterial wall inflammation, driving the development of atherosclerosis.Patients with T1D (n = 41), and healthy age-, sex-, and body mass index-matched controls (n = 20) were recruited. Arterial wall inflammation and haematopoietic activity were measured with 2'-deoxy-2'-(18F)-fluoro-D-glucose (18F-FDG) positron emission tomography/computed tomography. In addition, flow cytometry of circulating leucocytes was performed as well as targeted proteomics to measure circulating inflammatory markers. 18F-FDG uptake in the wall of the abdominal aorta, carotid arteries, and iliac arteries was higher in T1D compared with that in the healthy controls. Also, 18F-FDG uptake in the bone marrow and spleen was higher in patients with T1D. CCR2 and CD36 expressions on circulating monocytes were higher in patients with T1D, as well as several circulating inflammatory proteins. In addition, several circulating inflammatory markers (osteoprotegerin, transforming growth factor-alpha, CX3CL1, and colony-stimulating factor-1) displayed a positive correlation with FDG uptake. Within T1D, no differences were found between people with a high and low HbA1c.These findings strengthen the concept that chronic hyperglycaemia in T1D induces inflammatory changes that fuel arterial wall inflammation leading to atherosclerosis. The degree of hyperglycaemia appears to play a minor role in driving this inflammatory response in patients with T1D.
Gastrointestinal endoscopy devices and the European Union Medical Device Regulation: European Society of Gastrointestinal Endoscopy (ESGE) Position Statement
Authors: Michael Bretthauer, Yuichi Mori, Jasmin Zessner-Spitzenberg, Michal F. Kaminski, Peter D. Siersema, Thierry Ponchon, Helmut Messmann, Ian M. Gralnek, Raf Bisschops, Cesare Hassan
Journal: Endoscopy (2023)

Gastrointestinal endoscopy is largely dependent on medical devices. The European Union (EU) has recently introduced stricter rules and regulations for the approval of medical devices. This has consequences both for endoscopists and for patients. The new regulations increase the need for clinical trials and observational studies for new and current devices used in endoscopy to ensure clinical benefit and reduce patient harm. European endoscopy environments should facilitate industry-sponsored clinical trials and registry studies to meet the demand for robust data on endoscopic devices as required in the new legislation. The European Society of Gastrointestinal Endoscopy (ESGE) will play an active role in the establishment of the new system.The EU is establishing independent expert panels for device regulation in gastroenterology and hepatology, including endoscopy, that are charged with assessing the requirements for device testing. The ESGE encourages endoscopists with expertise in the technical and clinical performance of endoscopy devices to apply for expert panel membership. The ESGE has provided information for interested endoscopists on the ESGE website. Private European companies called "notified bodies" are entitled to conduct device approval for the EU. The ESGE will actively engage with these notified bodies for topics related to the new endoscopy device approval process to ensure continued access to high quality endoscopy devices for endoscopists in Europe.
Help me manage my sickle cell pain
Authors: Mary Shaniqua
Journal: BMJ (2023)

Help me manage my sickle cell painMary shares her experience of living with sickle cell disease and the importance of empathy Mary ShaniquaI received a diagnosis of sickle cell disease when I was around 18 months old.I have since experienced very challenging symptoms and diagnoses, including avascular necrosis, iron overload, and pulmonary embolism.Changes in my body caused by sickle cell have also significantly affected my mobility and my social life.Experiencing a crisis is awful.The pain is excruciating.It feels like someone armed with knives in their hands and spikes on their feet jumping, stabbing, and stamping to their own rhythm inside a selected part of my body.The knives feel like they are deep within the epicentre of my bones and stabbing outwards, at every angle, in an attempt to escape; creating a piercing radiating pain.When I present to you in crisis, I am in agony.But you can help me through these difficult, traumatic-yet recurring-vulnerable periods in my life.
The causal relationship between gastro-oesophageal reflux disease and idiopathic pulmonary fibrosis: a bidirectional two-sample Mendelian randomisation study
Authors: Carl J. Reynolds, Fabiola Del Greco M, Richard J. Allen, Carlos Flores, R. Gisli Jenkins, Toby M. Maher, Philip L. Molyneaux, Imre Noth, Justin M. Oldham, Louise V. Wain, Jiyuan An, Jue-Sheng Ong, Stuart MacGregor, Tom A. Yates, Paul Cullinan, Cosetta Minelli
Journal: European Respiratory Journal (2023)

Background Gastro-oesophageal reflux disease (GORD) is associated with idiopathic pulmonary fibrosis (IPF) in observational studies. It is not known if this association arises because GORD causes IPF or because IPF causes GORD, or because of confounding by factors, such as smoking, associated with both GORD and IPF. We used bidirectional Mendelian randomisation (MR), where genetic variants are used as instrumental variables to address issues of confounding and reverse causation, to examine how, if at all, GORD and IPF are causally related. Methods A bidirectional two-sample MR was performed to estimate the causal effect of GORD on IPF risk and of IPF on GORD risk, using genetic data from the largest GORD (78 707 cases and 288 734 controls) and IPF (4125 cases and 20 464 controls) genome-wide association meta-analyses currently available. Results GORD increased the risk of IPF, with an OR of 1.6 (95% CI 1.04–2.49; p=0.032). There was no evidence of a causal effect of IPF on the risk of GORD, with an OR of 0.999 (95% CI 0.997–1.000; p=0.245). Conclusions We found that GORD increases the risk of IPF, but found no evidence that IPF increases the risk of GORD. GORD should be considered in future studies of IPF risk and interest in it as a potential therapeutic target should be renewed. The mechanisms underlying the effect of GORD on IPF should also be investigated.
Gut microbiota in COVID-19: new insights from inside
Authors: Bingqian Zhou, Xiaoqi Pang, Jingyi Wu, Tianyu Liu, Bangmao Wang, Hailong Cao
Journal: Gut Microbes (2023)

The epidemic of coronavirus disease-19 (COVID-19) has grown to be a global health threat. Gastrointestinal symptoms are thought to be common clinical manifestations apart from a series of originally found respiratory symptoms. The human gut harbors trillions of microorganisms that are indispensable for complex physiological processes and homeostasis. Growing evidence demonstrate that gut microbiota alteration is associated with COVID-19 progress and severity, and post-COVID-19 syndrome, characterized by decrease of anti-inflammatory bacteria like Bifidobacterium and Faecalibacterium and enrichment of inflammation-associated microbiota including Streptococcus and Actinomyces. Therapeutic strategies such as diet, probiotics/prebiotics, herb, and fecal microbiota transplantation have shown positive effects on relieving clinical symptoms. In this article, we provide and summarize the recent evidence about the gut microbiota and their metabolites alterations during and after COVID-19 infection and focus on potential therapeutic strategies targeting gut microbiota. Understanding the connections between intestinal microbiota and COVID-19 would provide new insights into COVID-19 management in the future.
Simulation-based estimates and projections of global, regional and country-level maternal mortality by cause, 1990–2050
Authors: Zachary J. Ward, Rifat Atun, Gary King, Brenda Sequeira Dmello, Sue J. Goldie
Journal: Nature Medicine (2023)

Abstract Maternal mortality is a major global health challenge. Although progress has been made globally in reducing maternal deaths, measurement remains challenging given the many causes and frequent underreporting of maternal deaths. We developed the Global Maternal Health microsimulation model for women in 200 countries and territories, accounting for individual fertility preferences and clinical histories. Demographic, epidemiologic, clinical and health system data were synthesized from multiple sources, including the medical literature, Civil Registration Vital Statistics systems and Demographic and Health Survey data. We calibrated the model to empirical data from 1990 to 2015 and assessed the predictive accuracy of our model using indicators from 2016 to 2020. We projected maternal health indicators from 1990 to 2050 for each country and estimate that between 1990 and 2020 annual global maternal deaths declined by over 40% from 587,500 (95% uncertainty intervals (UI) 520,600–714,000) to 337,600 (95% UI 307,900–364,100), and are projected to decrease to 327,400 (95% UI 287,800–360,700) in 2030 and 320,200 (95% UI 267,100–374,600) in 2050. The global maternal mortality ratio is projected to decline to 167 (95% UI 142–188) in 2030, with 58 countries above 140, suggesting that on current trends, maternal mortality Sustainable Development Goal targets are unlikely to be met. Building on the development of our structural model, future research can identify context-specific policy interventions that could allow countries to accelerate reductions in maternal deaths.
Collaboration between explainable artificial intelligence and pulmonologists improves the accuracy of pulmonary function test interpretation
Authors: Nilakash Das, Sofie Happaerts, Iwein Gyselinck, Michael Staes, Eric Derom, Guy Brusselle, Felip Burgos, Marco Contoli, Anh Tuan Dinh-Xuan, Frits M.E. Franssen, Sherif Gonem, Neil Greening, Christel Haenebalcke, William D-C. Man, Jorge Moisés, Rudi Peché, Vitalii Poberezhets, Jennifer K. Quint, Michael C. Steiner, Eef Vanderhelst, Mustafa Abdo, Marko Topalovic, Wim Janssens
Journal: European Respiratory Journal (2023)

Background Few studies have investigated the collaborative potential between artificial intelligence (AI) and pulmonologists for diagnosing pulmonary disease. We hypothesised that the collaboration between a pulmonologist and AI with explanations (explainable AI (XAI)) is superior in diagnostic interpretation of pulmonary function tests (PFTs) than the pulmonologist without support. Methods The study was conducted in two phases, a monocentre study (phase 1) and a multicentre intervention study (phase 2). Each phase utilised two different sets of 24 PFT reports of patients with a clinically validated gold standard diagnosis. Each PFT was interpreted without (control) and with XAI's suggestions (intervention). Pulmonologists provided a differential diagnosis consisting of a preferential diagnosis and optionally up to three additional diagnoses. The primary end-point compared accuracy of preferential and additional diagnoses between control and intervention. Secondary end-points were the number of diagnoses in differential diagnosis, diagnostic confidence and inter-rater agreement. We also analysed how XAI influenced pulmonologists’ decisions. Results In phase 1 (n=16 pulmonologists), mean preferential and differential diagnostic accuracy significantly increased by 10.4% and 9.4%, respectively, between control and intervention (p&lt;0.001). Improvements were somewhat lower but highly significant (p&lt;0.0001) in phase 2 (5.4% and 8.7%, respectively; n=62 pulmonologists). In both phases, the number of diagnoses in the differential diagnosis did not reduce, but diagnostic confidence and inter-rater agreement significantly increased during intervention. Pulmonologists updated their decisions with XAI's feedback and consistently improved their baseline performance if AI provided correct predictions. Conclusion A collaboration between a pulmonologist and XAI is better at interpreting PFTs than individual pulmonologists reading without XAI support or XAI alone.
Response to: Correspondence on "Testing different thresholds for patient global assessment in defining remission for rheumatoid arthritis: are the current ACR/EULAR Boolean criteria optimal?" by Studenic<i>et al</i>
Authors: Paul Studenic, Daniel Aletaha, Tanja A Stamm, Maarten de Wit, Diane Lacaille, Josef S Smolen, David Felson
Journal: Annals of the Rheumatic Diseases (2023)
Slow integrin-dependent migration organizes networks of tissue-resident mast cells
Authors: Lukas Kaltenbach, Paloma Martzloff, Sarah K. Bambach, Nadim Aizarani, Michael Mihlan, Alina Gavrilov, Katharina M. Glaser, Manuel Stecher, Roland Thünauer, Aude Thiriot, Klaus Heger, Katrin Kierdorf, Stephan Wienert, Ulrich H. von Andrian, Marc Schmidt-Supprian, Claus Nerlov, Frederick Klauschen, Axel Roers, Marc Bajénoff, Dominic Grün, Tim Lämmermann
Journal: Nature Immunology (2023)

Abstract Immune cell locomotion is associated with amoeboid migration, a flexible mode of movement, which depends on rapid cycles of actin polymerization and actomyosin contraction 1 . Many immune cells do not necessarily require integrins, the major family of adhesion receptors in mammals, to move productively through three-dimensional tissue spaces 2,3 . Instead, they can use alternative strategies to transmit their actin-driven forces to the substrate, explaining their migratory adaptation to changing external environments 4–6 . However, whether these generalized concepts apply to all immune cells is unclear. Here, we show that the movement of mast cells (immune cells with important roles during allergy and anaphylaxis) differs fundamentally from the widely applied paradigm of interstitial immune cell migration. We identify a crucial role for integrin-dependent adhesion in controlling mast cell movement and localization to anatomical niches rich in KIT ligand, the major mast cell growth and survival factor. Our findings show that substrate-dependent haptokinesis is an important mechanism for the tissue organization of resident immune cells.
Utility of flow cytometry screening before MRD testing in multiple myeloma
Authors: Vandana Panakkal, Arjun Lakshman, Min Shi, Horatiu Olteanu, Pedro Horna, Michael M. Timm, Gregory E. Otteson, Linda B. Baughn, Patricia T. Greipp, Wilson I. Gonsalves, Prashant Kapoor, Morie A. Gertz, Moritz Binder, Francis K. Buadi, Angela Dispenzieri, S. Vincent Rajkumar, Shaji K. Kumar, Dragan Jevremovic
Journal: Blood Cancer Journal (2023)
Non-driver mutations landscape in different stages of primary myelofibrosis determined ASXL1 mutations play a critical role in disease progression
Authors: Xin Yan, Zefeng Xu, Peihong Zhang, Qi Sun, Yujiao Jia, Tiejun Qin, Shiqiang Qu, Lijuan Pan, Zhanqi Li, Jinqin Liu, Zhen Song, Qingyan Gao, Meng Jiao, Jingye Gong, Huijun Wang, Bing Li, Zhijian Xiao
Journal: Blood Cancer Journal (2023)
How to save £20 000 and 780 staff hours a year on a single ward—by making one climate friendly change
Authors: Florence Wedmore
Journal: BMJ (2023)

Hospitals are finding that sustainable healthcare can bring triple wins—for the planet, for patients and staff, and for the bottom line. Involving staff and patients is key, as <b>Florence Wedmore</b> found out at the Royal College of Physicians’ conference last month
Chronic thromboembolic pulmonary hypertension and clot resolution after COVID-19-associated pulmonary embolism
Authors: Cindy M.M. de Jong, Chantal Visser, Remy H.H. Bemelmans, Wim G. Boersma, Bram van den Borst, J. Louise I. Burggraaf, Suzanne C. Cannegieter, Arina J. ten Cate-Hoek, F. Nanne Croles, Harald J. Faber, Laura M. Faber, Merel E. Hellemons, Lisa M. Hessels, Menno V. Huisman, Pieter W. Kamphuisen, Stephanie C.E. Koster, Lucia J.M. Kroft, Ivo van der Lee, Jenneke Leentjens, Karina Meijer, Maarten K. Ninaber, Brigitte M. Sondermeijer, Susanne Stads, Anton Vonk Noordegraaf, Kristien Winckers, Marieke J.H.A. Kruip, Frederikus A. Klok
Journal: European Respiratory Journal (2023)

<b>The results of this study suggest that CTEPH is not a more common long-term complication after COVID-19-associated PE than after PE in non-COVID-19 patients, and thrombus resolution did not seem to be different from non-COVID-19-associated PE</b> https://bit.ly/3IjvWL3
Hepatic Superscan in Methotrexate-Associated Lymphoproliferative Disorder
Authors: Tsz-Kit Chow
Journal: Clinical Nuclear Medicine (2023)

A 60-year-old man on methotrexate for treatment of adult-onset Still disease presented with acute onset of fever, pancytopenia, and deranged liver function. Besides FDG-avid lesions in spleen and skeleton, his 18 F-FDG PET/CT study showed diffuse and intense uptake in the liver with significantly suppressed heart and brain activity (reminiscent of a hepatic superscan). Subsequent biopsy confirmed the diagnosis of methotrexate-associated lymphoproliferative disorder.
Scarlett McNally: Let’s talk about contraception
Authors: Scarlett McNally
Journal: BMJ (2023)

Worldwide, 50% of pregnancies are unplanned. 1 In 2021 the number of women in England and Wales who had abortions reached a record 214 256, up by 16% since 2016. 2 Around a quarter of all pregnancies in the UK are terminated. 2 3The reasons for this are multifactorial, but if we want women and girls to have as much choice and autonomy as possible we must stop being so coy about sex, contraception, and sexual consent.